Androgen as a male contraceptive and non-contraceptive androgen replacement

ABSTRACT

The present invention relates to methods of providing male contraception using a specified androgen without the need of a separate sterilizing agent. The invention also describes methods for non-contraceptive androgen replacement and devices useful for carrying out both processes.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application is a divisional of U.S. application Ser.No. 09/154,283, filed on Sep. 16, 1998, and claims the benefit of U.S.Provisional Patent Applications Nos. 60/059,300 and 60/062,962, filedSep. 17, 1997, and Oct. 10, 1997, respectively, the disclosures of whichare hereby incorporated by reference herein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] Financial support for the invention described herein was receivedfrom the U.S. Agency for International Development under CooperativeAgreement No. DPE-3050-A-00-8059-00. Therefore, the U.S. Government mayhave certain rights in the invention.

FIELD OF THE INVENTION

[0003] The present invention relates to the fields of medicine andpharmaceutical science in providing androgen replacement methods of malecontraception and devices useful in accordance with those methods.

BACKGROUND OF THE INVENTION

[0004] Male contraception has been enigmatic. Mechanical devices offerreduced sensation and inconvenience. While they may be effective inreducing the transmission of sexually transmitted diseases, they mayalso be a source of friction in a relationship. Moreover, suchcontraceptive methods are not without a significant incidence offailure.

[0005] For these and other reasons, chemical methods, such as birthcontrol pills for women, have been a long sought after objective.However, chemical protocols for men have been plagued by their ownproblems. For example, the continuous administration of luteinizinghormone releasing hormone (LHRH) and its analogs have been proposed asan effective way of suppressing spermatogenesis. This is accomplished byblocking gonadotropin secretion. Implants that deliver LHRH and itsanalogs therefore represent a potential male contraceptive. However, theloss of gonadotropins results in diminished secretion of testosteronewhich, amongst other things, provides a diminished libido and potentialloss of sexual function. Therefore, along with the administration ofLHRH, or another sterilant, the art recognizes the need for theco-administration of an androgen. See U.S. Pat. No. 5,733,565. Anandrogen, often testosterone, is supplied to help bolster the body'stestosterone level and sustain normal sexual function. This sort ofandrogen supplementation, however, brings with it many problems of itsown. Testosterone is expensive and relatively large quantities need tobe administrated, usually by injection, on a daily basis. Testosteroneis also 5α-reduced to DHT (dihydrotestosterone) which is itself a verypotent agent. It can over-stimulate prostate growth, potentially leadingto complications such as BPH (benign prostate hypoplasia).

[0006] In view of the foregoing, there remains a need for an effectivemethod of male contraception with a minimum of health risks and furthercomplications. That need is satisfied by the present invention.

SUMMARY OF THE INVENTION

[0007] The present invention is based on, amongst other things, thediscovery that an androgen can be used alone as an effectivecontraceptive, not merely as an androgen supplement. By using anandrogen as a contraceptive, one is able to eliminate the need forcombination therapies using androgens and sterilants simplifyingcontraception and lowering costs dramatically. Moreover, the androgensused in accordance with the present invention not only act ascontraceptives, but also maintain male sexual function and desire,without the side effects and adversities realized by the administrationof 5α-reducible androgens such as testosterone.

[0008] In accordance with a preferred embodiment, the present inventionrelates to methods of male contraception which include administering toa non-sterile male subject a predetermined amount of an androgen whichis sufficient to render that male subject reversibly sterile. If thedosage forms used in the methods of the present invention are for dailydosing, then sufficient androgen must be provided for that day. If thedosage form is active over a plurality of days, then sufficient androgenmust be provided for the entire period. Stated another way, the amountof androgen administered must be sufficient to render the subjectsterile each day over the predetermined period of time.

[0009] The androgen, when provided in the amounts contemplated willresult in blood levels of luteinizing hormone (LH) and folliclestimulating hormone (FSH) of 2.5 International units/litre (“IU/L”) orless and blood levels of testosterone (T) of 10 nmol/L or less.Preferably, the androgen is a non 5α-reducible androgen, such as a7α-modified androgen. More preferably, the androgen, when provided inthe amounts contemplated, will result in blood levels of LH and FSH of2.0 IU/L or less and blood levels of T of 4 nmol/L or less. Mostpreferably, the androgen when provided in the amounts contemplated, willresult in blood levels of LH and FSH of 1.0 IU/L or less, and bloodlevels of T of 3 nmol/L or less. Assuming that the androgen used isMENT, a steady-state blood level of more than 1.0 nmol/litre (“nmol/L”)should result. Preferably, blood levels of MENT of 1.5 nmol/L and evenmore preferably of 2 nmol/L or more will result.

[0010] If the goal is to provide contraception over a period of sixmonths, then a sufficient amount of the androgen as described above mustbe supplied to the subject each day so as to ensure contraceptiveefficacy each day for six months. That means that the blood levelsshould, at least generally, be within the specified limits for LH, FSHand testosterone as discussed above. Of course, day-to-day variation isto be expected based on the subject, the mode of administration, and thelike. However, on balance, the subject should receive enough androgen,preferably each day, to ensure that over the six month period thesubject is, for all practical purposes, incapable of reproduction.

[0011] Dosage forms which contain a sufficient quantity of the specifiedandrogens are also contemplated. These dosage forms, unlike those thathave gone before, will provide sufficient androgen to be contraceptivelyeffective without also causing certain side effects such as, forexample, overstimulating the prostate. The dosage forms contemplatedinclude, without limitation, the androgen and a pharmaceuticallyacceptable carrier.

[0012] With the understanding that androgens can be used alone as acontraceptive also comes a new understanding of the use of androgens inandrogen replacement therapy. There are certainly instances when onewould wish to bolster or augment a subject's androgen level to provide acertain therapeutic effect, i.e., enhanced sexual drive, without alsoproviding contraception. Therefore, the present invention also relatesto methods of androgen replacement therapy which comprise theadministration of androgen to a male subject in an amount which issufficient to treat the subject's condition without beingcontraceptively effective. The androgen, when provided in the amountscontemplated in accordance with this aspect of the present invention,will result in blood levels of LH and FSH of greater than 2.5 IU/L andblood levels of testosterone of greater than 10 nmol/liter. Preferably,the androgen is a non-5α-reducible androgen such as a7α-modified-androgen. This means that the amount of androgen provided isless than that necessary to provide effective contraception, yetsufficient to provide some level of other therapeutic effect. Dosageforms useful in accordance with this aspect of the invention are alsocontemplated.

BRIEF DESCRIPTION OF THE DRAWINGS

[0013]FIG. 1—is a graph of the steady-state blood levels of MENT insubjects with either one, two or four MENT Ac implants. Values shown aremeans±SE. Data from three clinics are presented. FIG. 1a (Clinic 1),FIG. 1b (Clinic 2) and FIG. 1c (Clinic 3).

[0014]FIG. 2—is a graph of the effect of MENT Ac implants on serumlevels of LH. Values shown are means±SE.

[0015]FIG. 3—is a graph of the effect of MENT Ac implants on serumlevels of FSH. Values shown are means±SE.

[0016]FIG. 4—is a graph of the effect of MENT Ac implants on serumlevels of T. Values shown are means±SE.

[0017]FIG. 5—is a graph of the effect of MENT Ac implants on serumlevels of DHT. Values shown are means±SE.

[0018]FIG. 6—is a graph of the “average” daily in vivo release of MENTAc from either one, two or four MENT Ac implants recovered fromsubjects. Values are means±SE. Number shown in each bar graph indicatessample size.

[0019]FIG. 7—is a graph of the effect of MENT by intramuscular injection(im) on serum levels of LH in a first multi-dose study. Values shown aremeans±SE.

[0020]FIG. 8—is a graph of the effect of MENT by intramuscular injection(im) on serum levels of FSH in a first multi-dose study. Values shownare means±SE.

[0021]FIG. 9—is a graph of the effect of MENT by intramuscular injection(im) on serum levels of T, in a first multi-dose study. Values shown aremeans±SE.

[0022]FIG. 10—is a graph of the effect of MENT by intramuscularinjection on serum levels of LH in a second multi-dose study. Valuesshown are means±SE.

[0023]FIG. 11—is a graph of the effect of MENT by intramuscularinjection on serum levels of FSH in a second multi-dose study. Valuesshown are means±SE.

[0024]FIG. 12—is a graph of the effect of MENT by intramuscularinjection on serum levels of T in a second multi-dose study. Valuesshown are means±SE.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Before discussing the invention in detail, some definitions areappropriate. A “male subject,” in accordance with the present invention,is a male mammal. Preferably, however, a male subject is a human male.All dosages discussed herein relate to an “average” sized human male.However, dosages can be scaled accordingly, using known principals ofpharmacy, to accommodate other species of mammal.

[0026] A “non-sterile” male subject is a male subject capable ofproducing a sufficient quantity of viable sperm which, under the rightconditions, can lead to reproduction. A “sterile male” or “sterile malesubject” is a male who does not produce sperm, does not produce sperm insufficient quantity, or does not produce sufficient viable sperm so asto make reproduction difficult and preferably impossible. While anon-sterile man normally produces about 100 to 300 million sperm permilliliter of ejaculate, clinically sterile males generally produce lessthan about 3 million sperm per milliliter of ejaculate or less. While itis still possible, even at 3 million sperm per milliliter of ejaculate,to fertilize an egg; statistically speaking, the chances of thathappening are greatly reduced. Indeed, this level has been acknowledgedas “clinical sterility.” See “W.H.O. Laboratory Manual for theExamination of Human Semen and Sperm—Cervical Mucus Interaction,” 3d Ed.Cambridge Univ. Press, 1992.

[0027] It is a goal of one aspect of the present invention to providereversible sterility. “Reversible,” in the context of the presentinvention, means that once the methods of the present invention arediscontinued, a male subject previously undergoing treatment will bereturned to a condition which will permit reproduction under normalconditions. At the very least, the androgen will not present a continuedobstacle to reproduction after therapy is discontinued. Reversible doesnot necessarily mean instantaneous. Full potency may not be restored fordays or even weeks after treatment is discontinued.

[0028] “Androgen,” in accordance with the present invention, is anynatural or synthetic male sex hormone including analogs and saltsthereof which are pharmaceutically acceptable and which, whenadministered in accordance with the present invention, providecontraceptive efficacy. Contraceptive efficacy in accordance with thepresent invention can be defined by the level of sperm produced asdefined above in terms of sterility. However, preferably, contraceptiveefficacy and sterility are defined herein by the blood levels of certaincompounds normally found in the circulating blood of male subjects. Theandrogen, when provided in the amounts contemplated, will result inblood levels of LH and FSH of 2.5 IU/L or less and blood levels oftestosterone of 10 nmol/liter or less. More preferably, the androgen,when provided in the amounts contemplated, will result in blood levelsof LH and FSH of 2.0 IU/L or less and blood levels of testosterone of 5nmol/liter or less and even more preferably blood levels of LH and FSHof 1.5 IU/L or less and blood levels of testosterone of 4 nmol/liter orless. Most preferably, the androgen, when provided in the amountscontemplated, will result in blood levels of LH and FSH of 1.0 IU/L orless and blood levels of testosterone of 3 nmol/liter or less.

[0029] Preferably, the androgen used is a non-5α-reducible androgen.Testosterone is excluded by this definition as it is a 5α-reducibleandrogen, and as such, can produce higher levels of adverse side effectsthan equivalent potencies of other androgens as described. Its use wouldalso not lower serum testosterone levels. Non-5α-reducible androgensinclude, without limitation, 7α-modified-androgens. Examples of theseinclude 7α-alkyl-androgens such as7α-methyl-14-dehydro-19-nortestosterone (CDB-868B),7α-methyl-17aβ-propionyloxy-D-homoestra-4, 16, dien-3-one (CDB 2322A)and 7α-methyl-19-nortestosterone (MENT) and their pharmaceuticallyacceptable salts. See Kumar et al., “The Biological Activity of7α-Methyl-19-Nortestosterone Is Not Amplified in Male Reproductive Tractas is That of Testosterone,” Endocrinology, Vol. 130, No. 6, pgs.3677-3683 (1992). The preferred androgen is MENT, its acetate, MENT Acand related compounds.

[0030] Other androgen compounds useful in the method of the inventionare testosterone derivatives having a non-hydrogen substituent in the 6αor 7α position. As used in the application, the term testosteronederivatives encompasses compounds having the basic four ring structureof testosterone, optionally modified at the 3, 5, 9, 11, 17 or 19positions. Examples of such compounds include:

[0031] 7-α-methyl testosterone,

[0032] 7-α-methyl-11β-hydroxytestosterone,

[0033] 7-α,17-dimethyltestosterone,

[0034] 7-α,17-dimethyl-11β-hydroxytestosterone,

[0035] 7-α,17-dimethyl-19-nortestosterone,

[0036] 7-α,17-dimethyl-11β-hydroxy-19-nortestosterone,

[0037] 6-α,17-methyl testosterone,

[0038] 6-α,17-methyl-19-nortestosterone,

[0039] 6-α,17-methyl-11β-hydroxytestosterone,

[0040] 6-α,17-dimethyltestosterone,

[0041] 6-α,17-dimethyl-11β-hydroxytestosterone,

[0042] 6-α,17-dimethyl-19-nortestosterone, and

[0043] 6-α,17-dimethyl-11β-hydroxy-19-nortestosterone

[0044] The 7α-methyl testosterone compounds for use in the invention canbe prepared as described in U.S. Pat. No. 3,341,557 which isincorporated herein by reference. Synthesis of the other compoundidentified herein have also been described in the literature.

[0045] Preferably, the androgens used should have a minimum of sideeffects. One method of determining the degree of side effects exhibitedby a particular androgen is by measuring its ability to stimulate theprostate. Compounds such as testosterone can overstimulate the prostate.MENT, however, stimulates the prostate to a much lower degree,particularly in the potency ranges contemplated as part of the presentinvention. Indeed, as shown in FIG. 5, levels of the metabolite DHTactually decreased along with the levels of LH, FSH and testosteronesince, by use of the present invention, the bodies production oftestosterone is reduced.

[0046] The “predetermined amount” or “amount” of androgen as used inaccordance with the present invention can vary widely, depending on anumber of factors known to practitioners of the medical andpharmaceutical sciences. The predetermined amount can depend on factorssuch as the size, weight, hormone level and age of the subject, thesubject's sperm count, the type of androgen used, the possibility ofinteractions with other therapies and the type of dosage form used. Forexample, more androgen may need to be administered to a subjecttransdermally to arrive at the appropriate blood level when compared tothe IV administration of the same androgen. In addition, the propertiesof a salt form of an androgen may affect the transdermal qualities of adrug when compared to other forms of the same androgen.

[0047] Also important to a determination of the amount of androgen to bedelivered each day is the objective. More androgen is needed forcontraception than non-contraceptive androgen replacement. Because ofthe wide variation in these factors, factors which will vary from dosageform to dosage form, from androgen to androgen and from subject tosubject, it is far more convenient to describe the amount of androgenuseful in terms of the amount of a particular androgen which isnecessary to produce certain levels of various chemicals in the subject,on average, each day of treatment. As previously discussed, when theobjective is male contraception, the amount contemplated, will result inblood levels of LH and FSH of 2.5 IU/L or less and blood levels oftestosterone of 10 nmol/liter or less. At these levels, on the average,a person has been provided with an amount of androgen necessary toprovide a contraceptive effect each day, i.e., over a 24 hour period. Ifnon-contraceptive androgen replacement is the object, then blood levelsof LH, FSH, and testosterone should be higher than 2.5 IU/L and 10nmol/liter respectively.

[0048] A “predetermined time” in accordance with the present inventionis preferably at least a plurality of days and preferably, at leastseven days. Even more preferably, the amount of androgen administeredwill be sufficient to provide contraceptive efficacy each day over a 30day period of time and most preferably over at least about 180 days.Thus, when a device is to be used to provide contraception over apredetermined time of about 180 days, for example, the device mustcomprise sufficient androgen to provide the desired blood levels of LH,FSH and testosterone each day over that period of time. Of course, itmay take 30 or more days before the administration of androgen at thelevels described herein is contraceptively effective.

[0049] Using MENT Ac as a more specific example, an implantable rod, asdescribed in the examples, which is capable of releasing about 500micrograms of MENT Ac over about 24 hours, and which contains sufficientMENT Ac to provide about 500 micrograms of MENT each day for about 28days, (see FIG. 6) can produce daily blood levels of LH which averagebelow about 2 IU/L, levels of FSH which average just above about 2 IU/Land levels of testosterone of about 5.0 nmol/liter. See FIGS. 2-4 whichrespectively show the blood levels of LH, FSH and testosterone resultingfrom the administration of various daily amounts of MENT Ac. The “opensquares” connected by a line represent the blood levels resulting fromthe use of a single implant as described above. As shown in FIG. 1,serum levels of MENT of between 1.0 and 2.0 nmol/L also resulted fromthe use of a single implant. The use of two such implantssimultaneously, (FIGS. 2-4 and the “closed circles” connected by a line)or the use of a single implant which could introduce about 1,000micrograms of MENT Ac into a subject's blood each day as described canproduce daily blood levels of LH which average less than 0.5 IU/L,levels of FSH which average just above less than 0.5 IU/L and levels oftestosterone of about 1.0 nmol/liter. Serum levels of MENT were, onaverage, between about 2.0 and about 2.5 nmol/L. See FIG. 1.

[0050] As demonstrated in FIGS. 2-4, the use of additional MENT Ac fromimplanted, continuous release rods, over 1000 micrograms per day, didnot result in significantly lower levels of LH, FSH or testosterone. Thesimultaneous use of four 500 microgram per day implants resulted inlevels of LH, FSH and testosterone which were very comparable to thoseobtained at the 1000 microgram per day level. That means that forMENT/MENT Ac, the amount of androgen which should be administered to asubject each day for the entire length of treatment should vary frombetween about 200 to about 2000 micrograms. More preferably, the amountof MENT administered each day will range from between about 400 andabout 1500 micrograms and even more preferably, the amount of MENTadministered each day will range from between about 500 to about 1000micrograms per day.

[0051] As Example 2 demonstrates, the rate of administration may also beimportant in determining the amount of androgen which needs to beadministered. An implant can administer 1000 micrograms of MENT Ac atroughly a constant rate over the course of 24 hours each day. However,when an equal dose of MENT, 1 mg, was administered by i.m. injection,the results, at least in terms of testosterone, were inadequate forcontraceptive purposes. While the full 1 mg would make it to the bloodstream, additional MENT was necessary to ensure that throughout a 24hour period, the steady state blood levels are maintained sufficientlyhigh, i.e. at a constant serum level comparable to that obtained bydosing the same amount using an implant.

[0052] As shown in FIGS. 9 and 12, for example, the use of 4 mg of MENTby once-a-day, i.m. injection is sufficient to ensure that some level ofeffective contraception is obtained. Without wishing to be bound by anyparticular theory, it is believed that at that level, for example, bloodlevels of MENT remain sufficiently high throughout the day to provideeffective contraception roughly equivalent to that which is obtained bythe use of 500 microgram MENT Ac implants as illustrated in FIGS. 2through 4. Therefore, the term “bioavailable amount” as used hereinmeans an amount sufficient so as to provide minimum steady state bloodlevels of LH, FSH, and testosterone falling within the levels discussedherein and effective to provide contraception. The amount of drugprovided in a once-a-day, non-sustained release system may need to besignificantly higher than needed for constant release dosage forms toprovide comparable minimum steady state drug levels comparable to thatobtainable by an implant or other long-term constant release systems inaccordance with the present invention throughout a 24 hour day cycle.

[0053] The amounts of other androgens necessary to provide the desiredblood levels of LH, FSH and testosterone will vary as previouslydescribed. However, the amounts can be simply determined byadministering a fixed amount of an androgen and measuring the resultingblood levels of LH, FSH and testosterone using conventional,commercially known techniques. Once the blood levels of these compoundshave been determined, the amount of androgen administered can beadjusted accordingly, either higher or lower, to provide the desiredblood levels of LH, FSH and testosterone.

[0054] LH, FSH and testosterone are more than mere markers indicatingsomething about the behavior and bioavailability of the androgen. Theyare each important in sperm production. LH stimulates Lydig cells torelease testosterone. Testosterone is important for spermatogenesis. FSHstimulates germ cells. If germ cells are present, but insufficienttestosterone is available, spermatogenesis is depressed. The reverse isalso true. In accordance with the present invention, sperm production iscompromised in two ways. Since FSH is reduced, so too are germ cells.Moreover, the reduction is LH and testosterone inhibits spermatogenesis.Yet, sexual function is maintained and potential side effects reduced oreliminated.

[0055] This underscores the importance of using androgens other thantestosterone. The use of testosterone is actually counterproductive asit elevates blood testosterone levels and may help supportspermatogenesis of any available germ cells.

[0056] The methods of the present invention can be practiced usingconventional dosage forms and techniques. First, one must select thetype of therapy desired, either contraception or non-contraceptiveandrogen replacement. To a large degree, the objective, the physicalcondition of the patient, and the dosage form will dictate the amount ofandrogen. Generally, more androgen is needed for contraceptive methods,less for non-contraceptive androgen replacement. The androgen selectedwill also be important in determining the dose as will the route ofadministration. Once the objective, the androgen and the desired routeare selected, the androgen can be administered in conventionalformulations and blood tests can be given to confirm the resulting bloodlevels of androgen, LH, FSH and testosterone. If the levels need to beadjusted, then the amount of androgen can be changed, another androgencan be selected or another dosage form can be employed.

[0057] For example, if a subject is to be given 500 micrograms of MENTper day via a once-a-day transdermal patch, a new patch must be providedand applied to the skin of the subject at about the same time each day.The patch may contain an excess of MENT. But the amount that isbioavailable is 500 micrograms. There may also be an initial burst ofandrogen when the patch is first applied, but the rate of delivery willadjust to a more constant rate and the average amount which isbioavailable should fall within the ranges described. If the steadystate blood levels are, on average over the day, too low, i.e., theblood levels of LH and FSH are above 2.5 IU/L and the level oftestosterone is above 10 nmol/liter, (or above some lower level asdescribed depending on the needs of the subject and the objective of thedoctor), several options are open. Subsequent doses administered by atransdermal patch can be increased, the dosage form can be changed to,for example, a subcutaneous implant and/or a more potent androgen, onewhich is compatible with the pharmaceutical carrier and preferablynon-5α-reducible, can be used. What is important is the long termmaintenance of blood levels of LH, FSH and testosterone below certainlimits. Therefore, when using MENT transdermal patches for that purpose,what is important is that minimum steady state blood levels of theandrogen be comparable to those which result from the use of MENT orMENT Ac containing subdermal implants as discussed herein and asdescribed in the examples.

[0058] Dosage forms which contain a sufficient quantity of the correctandrogen are also contemplated. These dosage forms, unlike those thathave gone before, will provide sufficient androgen to be contraceptivelyeffective without significant side effects. The dosage formscontemplated include, without limitation, the androgen and apharmaceutically acceptable carrier.

[0059] Pharmaceutically acceptable carriers, in the case of the presentinvention, can include, without limitation, chemical formulations suchas creams, salves, lotions, liquids, gels injectable liquids, liquidscapable of IV or IP administration, capsules and/or tablets capable ofdelivering androgen over an immediate period or over an extended periodof hours or days, as well as devices such as transdermal patches, pumpsand implants. Pumps and implants can be subcutaneous or implantableelsewhere and can include both errodable and diffusion-based devices, aswell as any other functionally equivalent devices known in the art.These can all be made and administered in accordance with procedureswell known in the industry.

[0060] Intravenous or injectable dosage forms can be comprised of anysuitable liquid carrier which can dissolve or sufficiently emulsify theandrogen to allow for safe administration. Often these formulations canalso include viscosity modifiers, surfactants, preservativessolubilizing agents, diluents and additives useful for rendering thesolutions isotonic. Other drugs or pharmaceuticals can also beadministered along with the androgen from the same dosage form.

[0061] Topical dosage forms can include androgen formulated in a lotion,cream, salve, paste or gel. Any such topical vehicle known in the artmay be used so long as it is capable of administering a suitablequantity of androgen in accordance with the present invention. Oftenthese formulations can also include viscosity modifiers, surfactants,preservatives, solubilizing agents, diluents, permeation enhancers,colors, fragrances and skin care additives like conditioners andhumectants. Other drugs or pharmaceuticals can also be administeredalong with the androgen from the same dosage form. These topicalformulations can include buccal dosage forms as well.

[0062] In accordance with the present invention, androgen can also beadministered through oral dosage forms such as liquids, oralsuspensions, elixirs, syrups, capsules, caplets or tablets. Anyformulation which can administer the dosage form orally is contemplatedincluding immediate release and sustained release dosage forms. Oftenthese formulations can also include viscosity modifiers, surfactants,preservatives solubilizing agents, microcapsules, microparticles,granules, diluents, binders, fillers, lubricants, colors, flavors andthe like. Other drugs or pharmaceuticals can also be administered alongwith the androgen from the same dosage form.

[0063] Finally, in a preferred aspect of the present invention, animplant or pump may be used. Implants include implantable subcutaneousdevices such as those disclosed in U.S. Pat. No. 5,733,565, the text ofwhich is hereby incorporated by reference. However, in accordance withthe present invention, the implant (or implants) are designed to providesufficient androgen to provide contraception. Therefore, when MENT Ac isused, for example, the implants will be capable of providing at leastabout 500 micrograms per day, each day for at least 30 days andpreferably about 180 days. Preferably, the amount of MENT Acadministered each day would not be greater than about 2000 microgramsper day and more preferably no more than 1000 micrograms. If MENT Acwere used in androgen replacement implants where contraception was notdesired, these same implants would generally provide less than about 500micrograms of MENT each day. While implants of this type are preferred,any similar devices designed to remain in the body and administer, in asnearly a uniform manner as possible, an amount of, in this case, anandrogen as described herein may be used. These implants can be producedand administered as known in the art. It should be noted that MENT Ac isreadily hydrolyzed to MENT and it has been found that MENT Ac issuperior in terms of bioavailability in certain subcutaneous implants asdiscussed in the examples. MENT may be preferred in other implants andMENT is preferred for transdermal dosage forms.

[0064] It will be appreciated that techniques for the administration ofvarious drugs, including such structurally similar compounds assteroids, are well known in the art. Therefore, it is unnecessary todescribe in detail administration details for oral, topical, IV andimplantation techniques. Any conventional technique or dosage form issuitable provided that it can reliably administer the correct amount ofthe androgens in question. Knowing the objective (contraception ornon-contraceptive androgen replacement), the types of androgens usefulin accordance with the present invention, the blood levels of variouscompounds desired consistent with that objective and methods ofdetermining the blood levels of important compounds as indicated willallow for one to practice the invention with any dosage form or dosingtechnique.

EXAMPLE 1

[0065] Forty-five healthy, normal male subjects were selected for astudy of the contraceptive effect of androgens alone. Subjects weretreated over the course of four weeks, during which extensive bloodwork-ups were undertaken. The subjects were divided into three groups of15 each. Group A received one subcutaneous implant, Group B received twosubcutaneous implants and Group C received four subcutaneous implants.Implants remained in place for 28 consecutive days. The implants weremanufactured by the Center for Biomedical Research and the PopulationCouncil of New York, 1230 York Avenue, New York, N.Y. 10021 and eachimplant had a length of 4.4 cm, a drug load per implant of 112±4 mg ofMENT Ac and a release rate of approximately 500 micrograms per implantper day, based on an in vivo study.

[0066] The procedure for production of the implants involved three basicsteps. In brief, cores were prepared containing 60% w/w of MENT Ac and40% w/w of Ethylene Vinyl Acetate copolymer (EVA); 25% w/w of VAcontent. The cores were then encased in EVA (9% VA content) and the endsof the tubing were sealed with melted EVA (25% VA content).

[0067] Preparation of cores containing 60% of MENT Ac

[0068] 1.5 g of EVA pellets (25% VA) was weighed into 18 ml of methylenechloride and dissolved overnight. 2.225 g of MENT Ac was weighed andadded to the solution of EVA in methylene chloride and Vortexed for 3minutes to mix. The methylene chloride was evaporated under vacuum, atroom temperature, for 2 hours. 2.3 g of the resulting solid dispersionwas obtained. This solid dispersion was filled into a stainless steelsyringe and heated to 120° C. for 5 minutes using the thermostaticallycontrolled heating jacket for the syringe. The solid dispersion was thenextruded by pressing the syringe, using the small laboratory press, intoa brass mold with grooves of 2.38 mm diameter and 4.5 cm length. Themold was opened and the cores cut into 4 cm pieces. The cores wereweighed individually and any core deviating from the mean weight by±7.5% were discarded. Cores were taken at random and tested for MENT Accontent using known methods. The mean value must not differ from theexpected values by more than ±7.5% and none of the individual values maydiffer from the mean by more than 10%.

[0069] Encasement of the core rods by EVA tubing

[0070] EVA (9% VA) tubing (about 2.55 mm in diameter) was cut into 5 cmlengths and soaked in methylene chloride for about 1-3 minutes. Each ofthe 4 cm core rods was introduced into one of the soaked 5 cm pieces ofEVA tubing leaving about 0.5 cm empty on both ends and left overnight toget rid of any residual methylene chloride.

[0071] Sealing of the two ends of the filled tubing

[0072] About 2 g of EVA (25% VA) was heated in the stainless steelsyringe equipped with the thermostatically controlled heating jacket for5 minutes at 120° C. The melted EVA was then injected into both ends ofeach filled tubing. The implants were heat sealed at 70° C. for 10minutes to enhance the adherence between the inside core and the outsidetubing and to ensure complete removal of any residual methylenechloride.

[0073] The total duration of the study was 42 days. Each man included inthe study was assessed through a medical history and a complete generalphysical examination and a determination of general eligibility.Subjects were tested on a weekly basis for six consecutive weeks atapproximately the same time each day. Day 1 was the date of thesubdermal implant's insertion and Day 29 was removal. On the last day ofthe study, Day 43, subjects received a general physical examination, aswell as an additional battery of blood tests. Blood samples for hormoneimmuno assays MENT (7 mL), FSH, LH and testosterone (5 mL for the last 3hormones together) were obtained during pre-admission and eachsubsequent visit.

[0074]FIG. 2 illustrates the effect of MENT Ac implants on mean serum LHconcentration. By the first post implant visit on day 8, levels of LHhad already dropped significantly. In fact, subjects to whom 2 or 4implants (500 micrograms each) were administered had nearly undetectablelevels of LH. By suppressing LH, testosterone production is suppressed.This is demonstrated in FIG. 4 which illustrates the effect of MENT Acimplants on the mean serum T concentration (testosterone). Again,subjects to whom two or four implants had been administered exhibitedvery low testosterone levels. Subjects who received a single implantstill showed much reduced levels of testosterone. A reduction intestosterone reduces or eliminates spermatogenesis. However, becauseandrogen is being supplied, sexual function is generally maintained.

[0075] Finally, FIG. 3 illustrates the effect of MENT Ac implants on themean serum FSH concentration. The use of the androgen containingimplants had a significant impact on the serum FSH concentration insubjects. FSH stimulates germ cell production. If germ cells arepresent, but testosterone is insufficient, then spermatogenesis cannottake place and sperm cells will not be produced. Similarly, if FSHconcentrations are low enough, germ cells will not be produced andspermatogenesis cannot take place irrespective of testosterone levels.Without wishing to be bound by any theory of operation, by the use ofandrogen, in accordance with the present invention, sperm production canbe controlled by effectively reducing both effective testosterone levelsand germ cell production.

EXAMPLE 2

[0076] Two multiple injection studies were undertaken in which groups offour normal, non-sterile men each received 1, 2 or 4 mg of MENT daily byintra-muscular (i.m.) injection for six consecutive days (24 men, 12 ineach study). The formulation in each injection included the appropriateamount of MENT suspended in 27.6 mg/mL of polyethylene glycol, 1.8 mg/mLof Tween 80 and 8.3 mg/mL of sodium chloride. Serum FSH, LH andtestosterone levels were measured daily. The results are illustrated inFIGS. 7-12.

[0077] In both studies, all three doses of MENT caused a gradualdecrease in serum gonadotropins and testosterone levels which reachedtheir lowest levels by the end of treatment at six days. The valuesreturned to the normal range by day 15-30 of the study period. Withreference to FIG. 8 (open boxes connected by a line=1 mg, closed boxesconnected by a line=2 mg, open circles connected by a line=4 mg) a doseof at least 4 mg was required to obtain serum levels of FSH below twointernational units (“IU”) per liter by day 6. This must be comparedwith the results obtained by the use of 1000 μg (1 mg) of the sameandrogen delivered by a subcutaneous implant as illustrated in FIGS. 2-4and Example 1. Therefore, considerably more of this same androgen wasrequired to obtain certain depressed serum levels of LH, FSH andtestosterone in males when the androgen was administered through aonce-a-day intra-muscular injection when compared to continuous releaseimplants. Indeed, depending upon the level of LH, FSH and testosteronedesirable by a particular health care professional, a dose significantlyin excess of 4 mg may be necessary for this type of dosage form. FIG. 7illustrates the level of serum LH achieved in the first study and FIG. 9illustrates the level of serum testosterone achieved. FIGS. 10-12illustrate the levels of LH, FSH and testosterone realized by the sameprotocol at the second testing site. Both the data and the overalltrends of both studies are largely the same.

[0078] Although the invention herein has been described with referenceto particular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It is therefore to be understood that numerousmodifications may be made to the illustrative embodiments and that otherarrangements may be devised without departing from the spirit and scopeof the present invention as defined by the appended claims.

1. A male contraceptive comprising: at least a predetermined amount ofan androgen which is sufficient to render said male subject reversiblysterile for a predetermined period of time and which provides said malesubject with blood levels of LH and FSH of 2.5 IU/L or less andtestosterone of 10 nmol/liter or less and a pharmaceutically acceptablecarrier.
 2. The male contraceptive of claim 1 wherein said predeterminedamount of an androgen is sufficient provides said male subject withblood levels of LH and FSH of 2.0 IU/L or less and testosterone of 5nmol/liter or less.
 3. The male contraceptive of claim 2 wherein saidpredetermined amount of an androgen is sufficient provides said malesubject with blood levels of LH and FSH of 1.5 IU/L or less andtestosterone of 4 nmol/liter or less.
 4. The male contraceptive of claim3 wherein said predetermined amount of an androgen is sufficientprovides said male subject with blood levels of LH and FSH of 1.0 IU/Lor less and testosterone of 3 nmol/liter or less.
 5. The malecontraceptive of claim 2 wherein said predetermined period is at least30 days.
 6. The male contraceptive of claim 5 wherein said predeterminedperiod is at least 180 days.
 7. The male contraceptive of claim 4wherein said predetermined period is at least 30 days.
 8. The malecontraceptive of claim 7 wherein said predetermined period is at least180 days.
 9. The male contraceptive of claim 1 wherein saidpharmaceutically acceptable carrier is suitable for injection orintravenous administration.
 10. The male contraceptive of claim 1wherein said pharmaceutically acceptable carrier is suitable for topicalapplication.
 11. The male contraceptive of claim 1 wherein saidpharmaceutically acceptable carrier is a cream, lotion, gel or atransdermal patch.
 12. The male contraceptive of claim 1 wherein saidpharmaceutically acceptable carrier is suitable for administrationorally.
 13. The male contraceptive of claim 1 wherein saidpharmaceutically acceptable carrier is an implant or pump.
 14. A malecontraceptive comprising: a predetermined amount of a non-5α-reducibleandrogen which is sufficient to render said male subject reversiblysterile for at least one day and a pharmaceutically acceptable carrier.15. The male contraceptive of claim 14 wherein said non-5α-reducibleandrogen is MENT, MENT Ac or salts thereof provided in a bioavailableamount of between about 500 and about 1000 micrograms per day.
 16. Themale contraceptive of claim 15 wherein said pharmaceutically acceptablecarrier is selected from the group consisting of an implant, a topicalgel and a transdermal patch.
 17. A method of androgen replacementtherapy comprising the step of: administering to a male subject anamount of an androgen which is sufficient to provide therapeuticefficacy without causing sterility.
 18. The method of claim 17 whereinsaid androgen is provided in an amount which is sufficient to maintainblood levels of LH and FSH above 2.5 IU/L and testosterone above 10nmol/liter.
 19. The method of claim 18 wherein said androgen is not5α-reducible.
 20. The method of claim 19 wherein said androgen is MENT,MENT Ac, or salts thereof provided in a bioavailable amount of betweengreater than zero and less than about 500 micrograms per day.
 21. Adosage form for androgen replacement therapy comprising an amount of anandrogen which is sufficient to provide therapeutic efficacy withoutcausing sterility and a pharmaceutically acceptable carrier.
 22. Thedosage form of claim 21 wherein said androgen is provided in an amountwhich is sufficient to maintain blood levels of LH and FSH above 2.5IU/L and testosterone above 10 nmol/liter.
 23. The dosage form of claim22 wherein said androgen is not 5α-reducible.